TABLE 1.

Chondroprotective therapeutics and the underlying mechanism of action targeting aging and degeneration associated determinants.

Categories of therapeutic strategies	Therapeutics	Therapeutic mechanism	References
Natural products/nutrients and their derivatives	Ascorbic acid	• Protection for human chondrocytes against oxidative stress	Chang et al., 2015
	Baicalin	• Prevented the apoptosis of endplate chondrocytes by inhibiting the oxidative stress • Inhibited endoplasmic reticulum stress •Protects human OA chondrocytes against IL-1β-induced apoptosis •Protects the degradation of ECM through activating autophagy via miR-766-3p/AIFM1 axis	Pan et al., 2017; Cao et al., 2018; Li et al., 2020
	Curcumin	• Protected the mitochondrial function, hence prevented cartilage degeneration •improves age-related and surgically induced osteoarthritis by promoting autophagy •Inhibited apoptosis of chondrocytes through activation ERK1/2 signaling Pathways induced autophagy •Inhibited the PERK-eIF2α-CHOP pathway through promoting SIRT1 expression in oxidative stress	Li et al., 2017; Feng et al., 2019; Nicoliche et al., 2020
	Delphinidin (a primary plant pigment, and also an antioxidant)	• Cytoprotects chondrocytes against oxidative stress through activation of autophagy	Lee et al., 2020
	Diosmin	• Chondroprotective effect via modulating oxidative stress	Yi−Ru Chen et al., 2019
	Polyphenols derived by olive extracts (e.g., Oleuropein)	Targeted Cx43 and senescence	Varela-Eirín et al., 2020
	Resveratrol	• Exerted anabolic, anti-catabolic, anti-inflammatory and chondroprotective effects •Delays cartilage degeneration autophagy via AMPK/mTOR pathway	Im et al., 2012; Qin et al., 2017
	Vitamin D	• Activated autophagy via mediating the AMPK–mTOR signaling pathway in chondrocytes, to reduce osteoarthritis	Kong et al., 2020
Pharmacological agents (biological factors/Drugs)	Irisin, a cleaved form of fibronectin type III domain containing 5 (FNDC5)	• Modulated Oxidative Stress •Regulated mitochondrial Integrity •Regulated autophagy	Wang et al., 2020
	Fenofibrate	• Senotherapeutic molecules with pro-autophagic activity	Nogueira-Recalde et al., 2019
	Navitoclax (ABT263)	• A specific inhibitor of the BCL-2 and BCL-xL proteins •Reduced inflammation •Senolytic drug	Yang et al., 2020
	Peroxiredoxin II (Prx II)	• Anti-oxidative stress and anti-aging effects •Reduced oxidative stress and cell senescence in chondrocytes by activating the p16-CDK4/6-pRb-E2F signaling pathway	Shao et al., 2020
	Rapamycin	• A specific inhibitor of the mTOR signaling pathway •Enhanced expression of autophagy regulators and prevents chondrocyte death.	Caramés et al., 2012; Pal et al., 2015; Bao et al., 2020
Biologics (cell-based)	Articular cartilage progenitors	• Resistance to telomere erosion through the expression of telomerase •Tissue replacement therapies	Dowthwaite, 2004; Williams et al., 2010; McCarthy et al., 2012; Jiang et al., 2016
	Adult stem cells (tissue-specific and mesenchymal stem cells)	• Reduced catabolic effect •Reduced inflammation—via their indirect regenerative effects (secretomes and EVs) •Immunomodulatory effect •Anti-apoptosis and anti-fibrosis •Tissue replacement therapies	Samuel et al., 2018; Samuel et al., 2019
	Embryonic stem cells/induced pluripotent stem cells	• Tissue replacement therapies	Chang et al., 2020; Gardner et al., 2019
Biologics (cell-free)	Platelet-rich plasma	• Reduced inflammation •Regulates cell chemotaxis •Improved angiogenesis •Enhanced cell proliferation and cell differentiation •Enhanced ECM production, hence matrix deposition	Moussa et al., 2017; Garbin and Olver, 2020
	Extracellular vesicles/exosomes	• Improved cartilage thickness •Increased matrix deposition •Better subchondral bone integrity •Reduced synovial cell apoptosis •Reduced MMPs	Wang et al., 2017; Khatab et al., 2018; Zhang et al., 2019; Jin et al., 2020